Substituted piperidine compounds have been used in the treatment of many nervous system disorders. One particular substituted piperidine compound proven useful in treating central nervous system disorders is dexmethylphenidate, which is often prescribed to control symptoms of attention deficit hyperactivity disorder (ADHD).
Dexmethylphenidate, also referred to as d-threo-methylphenidate and (2R,2′R)-(+)-threo-methylphenidate, is the d-threo stereoisomer of methylphenidate. Methylphenidate exists in four stereoisomeric forms: d-threo, l-threo, d-erythro and l-erythro. d-threo-methylphenidate and l-threo-methylphenidate are enantiomers, and l-erythro-methylphenidate and d-erythro-methylphenidate are enantiomers. However, preparing and isolating dexmethylphenidate in its pure stereoisomeric form, i.e., the d-threo stereoisomer, has proven to be difficult.
The preparations of enantiomerically pure dexmethylphenidate hydrochloride were reported by R. Rometsch in U.S. Pat. Nos. 2,838,519 and 2,957,880. According to the methods described by Rometsch, enantiomerically pure l-erytho-2-phenyl-2-(2-piperidyl)acetamide was first obtained by resolution of a racemic mixture of erythro-2-phenyl-2-(2-piperidyl)acetamide with d-(±)-tartaric acid in 96% ethanol. The enantiomerically pure l-erythro-2-phenyl-2-(2-piperidyl)acetamide was epimerized in aqueous potassium hydroxide to the d-threo-2-phenyl-2-(2-piperidyl)acetamide stereoisomer. d-threo-methylphenidate hydrochloride was then obtained upon hydrolysis and esterification of d-threo-2-phenyl-2-(2-piperidyl)acetamide.
The initial approach described by Rometsch was further optimized by Khetani et al. in PCT Patent Application Publication No. WO 98/52921 and Ramaswamy et al. in U.S. Pat. No. 5,965,734. Resolution of a racemic mixture of erythro-2-phenyl-2-(2-piperidyl)acetamide with d-(±)-tartaric acid in methanol afforded a 40% yield of 1-erythro-2-phenyl-2-(2-piperidyl)acetamide. Epimerization of l-erythro-2-phenyl-2-(2-piperidyl)acetamide with potassium tert-butoxide in toluene at 70° C. furnished d-threo-2-phenyl-2-(2-piperidyl)acetamide in 85% yield. d-threo-2-phenyl-2-(2-piperidyl)acetamide was converted to d-threo-methylphenidate hydrochloride upon treatment with concentrated sulfuric acid in refluxing methanol and hydrochloride salt in 80% yield.
Further, several methods have been reported for enriching the enantiomeric purity of dexmethylphenidate, with the first method being reported in 1987 by Patrick et al. J. Pharm. Exp. Ther. (1987) 241, 152-158, by crystallization of dexmethylphenidate from a mixture of methanol and ether. Novartis also reportedly increased the enantiomeric purity of dexmethylphenidate hydrochloride from 80% enantiomeric excess (e.e.) to greater than 98% e.e. by recrystallization from a 1:1.7 (v/v) mixture of methanol and t-butyl methyl ether (M. Prashad et al., Tetrahedron: Asymmetry (1998) 9, 2133-2136). PCT Patent Application Publication WO 98/25902 also reports an enrichment of the enantiomeric purity of dexmethylphenidate hydrochloride from this same solvent mixture. Although such attempts to enrich the enantiomeric purity of dexmethylphenidate hydrochloride by recrystallization do provide enantiomerically pure compound, recrystallization results in loss of yield and is not desirable for use with reactions that are performed on a large scale to obtain large quantities of the desired product.
An alternative approach to synthesizing enantiomerically pure d-threo-methylphenidate hydrochloride using an enantiomerically pure starting material, d-pipecolic acid, was reported by Thai et al. in J. Med. Chem. (1998) 41, 591-601. Enantiomerically pure d-pipecolic acid was obtained in 37% yield by recrystallization of the diastereomeric tartrate salt, followed by the separation of the desired amino acid from tartaric acid by ion-exchange chromatography. d-pipecolic acid was protected with a BOC group to afford N-BOC-d-pipecolic acid in 97% yield. The key amino ketone was prepared from N-BOC-d-pipecolic acid in two steps involving its conversion to the N-methoxy-N-methyl amide, followed by a reaction with the amide with phenyllithium. The amino ketone underwent a Wittig olefination with methyltriphenylphosphonium bromide in the presence of potassium tert-butoxide to give the alkene in high yield. The transformation of the obtained alkene to the desired alcohol as a racemic mixture of threo-stereoisomers via a hydroboration/oxidation reaction was critical to introducing the second stereogenic center. Hydroboration with BH3-THF gave a 72:28 mixture of threo and erythro isomers, respectively, from which the threo alcohol was isolated in 64% yield after chromatography. Oxidation of the threo alcohol with pyridinium dichromate (PDC) in dimethylformamide (DMF) followed by esterification of the resulting acid with diazomethane, and N-BOC group deprotection with 3 N methanolic hydrochloric acid furnished d-threo-methylphenidate hydrochloride in 67% yield after recrystallization from a mixture of ethanol and ether.
However, all of the aforementioned methods for obtaining dexmethylphenidate in its pure enantiomeric form require either recrystallization from a mixture of stereoisomers, or a large number of synthetic steps, both of which result in reduced yields. Thus, there is a need for improved methods of preparing dexmethylphenidate in its pure enantiomeric form and in high yield. Preferably, such methods are also adaptable to production on a large scale, which would have the advantage of providing a method for obtaining dexmethylphenidate in its pure enantiomeric form and in large quantities from a single reaction.